Epilepsy is a well-known neurological disease, found in about 3% of the population. Approximately 30% of patients with epilepsy do not respond to currently available therapies. Retigabine (N-[2-amino-4-(4-fluorobenzylamino) phenyl]carbamic acid, ethyl ester] (U.S. Pat. No. 5,384,330) has been found to be an effective treatment of a broad range of models of seizure disorders, and it appears to have an unusual mechanism of action. Bialer, M. et al., Epilepsy Research 1999, 34, 1-41; Wuttke, T. V., et al., Mol. Pharmacol. 2005, 67, 1009-1017. Retigabine has also been found to be useful in treating pain, including neuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003, 460, 109-116; Wickenden, A. D. et al., Expert Opin. Ther. Patents, 2004, 14(4).
“Benign familial neonatal convulsions,” an inherited form of epilepsy, has been associated with mutations in the KCNQ2/3 channels. Biervert, C. et al., Science 1998, 27, 403-06; Singh, N. A., et al., Nat. Genet. 1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55; Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequent investigations have established that one important site of action of retigabine is the KCNQ2/3 channel. Wickenden, A. D. et al., Mol. Pharmacol. 2000, 58, 591-600; Main, M. J. et al., Mol. Pharmacol. 2000, 58, 253-62. Retigabine has been shown to increase the conductance of the channels at the resting membrane potential, with a possible mechanism involving binding of the activation gate of the KCNQ 2/3 channel. Wuttke, T. V., et al., Mol. Pharmacol. 2005, op. cit. With increased sophistication of research in this area, retigabine has also been shown to increase neuronal M currents and to increase the channel open probability of KCNQ 2/3 channels. Delmas, P. and Brown, D. A. Nat. Revs Neurosci., vol. 6, 2005, 850-62; Tatulian, L. and Brown, D. A., J. Physiol., (2003) 549, 57-63.
The most therapy-resistant type of seizure is the so-called “complex partial seizure.” Retigabine has been found to be particularly potent in models for drug-refractory epilepsy. Retigabine is also active in several other seizure models. Because of retigabine's broad spectrum of activity and unusual molecular mechanism, there is hope that retigabine will be effective in management of several seizure types, including the complex partial seizure, and in treatment of hitherto untreatable forms of epilepsy. Porter, Roger J., Nohria, Virinder, and Rundfeldt, Chris, Neurotherapeutics, 2007, vol. 4, 149-154.
The recognition of retigabine as a potassium channel modulator has inspired a search for other—and, hopefully, better—potassium channel modulators among compounds with structural features similar to those of retigabine.